Clocks across taxa: Conserved circadian timekeeping mechanisms

地球围绕其轴线的自转导致环境的日常变化，影响着自地球上第一个生命以来的生物体的新陈代谢和生理。一种内源性的计时机制，即生物钟，进化成对每日周期的预测，并驱动昼夜节律，如动物的睡眠-醒来周期或植物的淀粉合成和降解。长期以来，时钟基因的节律表达被认为是导致节律性新陈代谢的原因，直到我们最近发现，在藻类和人类等各种生物中，时钟基因的节律对于某些代谢节律是必不可少的[1-2]。此外，我们发现代谢节律可以对全球基因表达节律做出贡献，将构成“时钟”的范式从仅包括基因表达网络转变为包括新陈代谢[3]。我们最近在《自然》杂志上报道，细胞内镁离子浓度的昼夜节律作为一种细胞自主计时机制，决定了单细胞藻类和人类细胞的关键时钟特性[3]。从机制上讲，我们发现这些节律提供了双向反馈，将节律代谢与时钟控制的基因表达联系起来。我们发现的新的代谢昼夜节律在真核生物的生命中是保守的，跨越了10亿年的进化。我们研究的一个关键方面是利用这种守恒性在“比较时间生物学”研究中发挥优势。对于这些研究，我们使用实验模型细胞来有效地测试最具刺激性的假说，并产生新的想法，这些想法随后可以转化为更复杂的有机体，如植物、哺乳动物或真菌。我们的模式真核生物物种--金黄色葡萄球菌--比任何其他类型的细胞都具有独特的优势。这种海藻是单细胞的，含有仅有8000个基因的单倍体基因组，细胞结构复杂程度较低。它生长方便，实验上高度驯化，现在是一个完善的昼夜节律时钟模型有机体。使用金黄色葡萄球菌，我们将解决一方面昼夜基因表达周期与最终促进有节奏的细胞生物学的生化机制之间的基本知识鸿沟。成功的候选人将加入我们的团队，获得在普通分子生物学、组织培养和生物化学技术方面的高度多样化的培训计划，以及时间生物学、广泛的体内荧光素酶成像、化学生物学和藻类转基因方法的特定实验设计。

Earth's rotation around its axis causes daily changes to the environment, influencing the metabolism and physiology of organisms since the first life on earth. An endogenous timekeeping mechanism, the circadian clock, evolved to allow anticipation of the daily cycle and drive circadian rhythms such as the sleep-wake cycle in animals or the synthesis and degradation of starch in plants.The rhythmic expression of 'clock genes' was long thought to cause rhythmic metabolism, until we recently established that clock gene rhythms are dispensable for some metabolic rhythms in organisms as diverse as algae and humans [1-2]. Moreover, we found that metabolic rhythms could contribute to global gene expression rhythms, shifting the paradigm of what constitutes 'the clock' from only gene expression networks to include metabolism [3]. We recently reported in Nature that circadian rhythms in the intracellular concentration of magnesium ions act as a cell-autonomous timekeeping mechanism, determining key clock properties both in a unicellular alga and in human cells [3]. Mechanistically, we found that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression.The novel metabolic circadian rhythms we identified are conserved across eukaryotic life, spanning over a billion years of evolution. A key aspect of our research is to use that conservation to our advantage in 'comparative chronobiology' studies. For these studies, we use experimental model cells to efficiently test the most stimulating hypotheses and generate new ideas that can subsequently be translated into more complex organisms such as plants, mammals, or fungi. Our model eukaryotic species, Ostreococcus tauri, offers unique advantages over any other cell type. This marine alga is unicellular, contains a haploid genome of only ~8000 genes, and a cellular structure of reduced complexity. It is convenient to grow, experimentally highly tractable, and now a well-established circadian clock model organism.Using Ostreococcus we will address the fundamental knowledge gap between circadian gene expression cycles on one hand, and the biochemical mechanisms that ultimately facilitate rhythmic cell biology on the other. The successful candidate will join our team and gain a highly diverse training programme in general molecular biology, tissue culture, and biochemistry techniques, as well as specific experimental design for chronobiology, extensive in vivo luciferase imaging, chemical biology, and transgenic approaches in algae.